3-amino-as-triazine substituted urea complexes and processes for preparing the same



United States Patent 0.

S-AMINO-AS-TRIAZINESUBSTlTUTED UREA COMPLEXES AND PROCESSES FOR'PREPAR- ING THE SAME Robert C. ONeill, New York, N. Y., and Arthur J. Basso,

Colonia, N. J., assignors to Merck & Co., Inc, Rahway, N. J a corporation of New Jersey No Drawing. Application March 10, 1955,

Serial No. 493,613 7 plexes with which this invention is. concerned may be represented by the following structural formula:

wherein R is hydrogen or a lower alkyl group, R is an electron withdrawing group and X is oxygen or sulfur.

These 3-amino-as-triazine-substituted urea complexes are new chemical compounds. They are equimolar com plexes which have their own characteristic properties that are markedly different from the component parts and are not mere mixtures of S-amino-as-triazihe and substituted urea compounds.

processes for preparing These novel 3-amino-as-triazinesubstituted urea complexes are produced by reacting a substituted urea com pound represented by the formulawherein R is hydrogen or a lower alkyl group, R is an electron withdrawing group, with a 3-amino.-astriazinc compound represented by the formula- R N\ I I N NHa wherein R is as above. I

The substituted urea compounds which may be erii ployed as one of the starting materials in this process are carbanilide compounds having an electron Withdrawing carbanilide compounds which may be employe'clinclude. 4,4 r dinitrocarbanilide'; Z-methyl-4,4-dinitrocarbanilide;

2,731,385 Patented Jan. 17, 1956 4-nitro-4'-cyanocarbanilide and 4-nitro-4'-acetocarbanilide.

The 3-amino-as-triazine which may be employed in this invention include 3-amino-as-triazine, 3-amino-5(6)- methyl-as-triazine, 3-amino-5,6-dimethyl-as-triazine.

In accordance with one procedure for carrying out the process of this invention the solid substituted urea compound is reacted with a solution of the Z-amino-as-triazine compound. The reaction mixture in which the substituted urea compound is ordinarily insoluble or very slightly soluble is stirred until the insoluble complex is formed. The insoluble 3-amino-as-triazinesubstituted urea complex is then filtered, washed and dried.

The reaction solvent is not critical. Ethers such as dioxane and ethyl ether, alcohols such as the lower aliphatic alcohols, hydrocarbons such as benzene, toluene, water or mixtures of such solvents may be employed satisfactorily. It has been found advantageous to employ a solvent in which the 3amino-as-triazine is soluble and in which the substituted urea is insoluble.

As the substituted urea compound it is preferred to employ 4,4-dinitrocarbanilide, although other carbanilides having diiferent electron withdrawing groups in the 4 and 4'-positions may be used. Typical substitutents which may be present in these positions are nitro, cyano, carboxyl and carboalkoxyl radicals. Furthermore, the electron withdrawing groups at the 4 and 4' positions need not be the same, thus typical examples of 4,4 disubstituted carbanilides useful in the invention are 4,4'-dinitrocarbanilide; 4,4'-dicyanocarbanilide and 4-nitro-4-cyanocarbanilide.

The 3-amino-as-triazinesubstituted urea complexes prepared in accordance with this invention are active against the widespread poultry disease commonly called Coccidiosis which is caused by species of protozoan parasites of the genus Eimeria. in this regard, E. tcnella is responsible for a severe and frequently fatal infection of the cecum of chickens. Furthermore, other serious infections are caused in fowl by other species of Eimeria and especially E. acervulina, E. necatrix, E. maxima, and E. 'brunezti. If left untreated, such infections often cause extensive losses of fowl. The elimination or control of coccidiosis is, therefore, of the utmost importance for successful poultry raising.

According to a further embodiment of this invention, novel compositions useful in the treatment of coccidiosis are provided containing the 3-amino-as-triazine'substituted urea complex as the active ingredient. These compositions comprise the 3-amino-as-triazine-substituted urea complex intimately combined with an inert carrier. In this regard compositions which contain a compound of the formula wherein R is hydrogen or lower alkyl groups, R is an These compositions comprise at least one of the 3-.

amino-as-triazine-substituted urea complexes mentioned above combined with an inert carrier or diluent. Such compositions are conveniently produced by intimately dispersing the active ingredient throughout a carrier. The carrier or diluent may be either liquid or solid. Liquid dispersions can be prepared satisfactorily by using emulsifiers and surface active agents. Any solid can be used as a carrier which is inert toward the active comvratio of carrier to active ingredient, compositions of vary 30 3 pounds and'which can be administered to animals with b. T88 pounds corn distiiie'rs dried grains (through 30 safety. Examples of suitable carriers are ground oyster mesh screen) 7 v shells, attapulgus clay and edible vegetable materials such 0. 487 pounds wheat shorts (30-80 mesh) as commercial animal and. poultry feeds, urea, corn d. 70 pounds dried vitamin B12 fermentation solubles meal ground corn,- citrus meal, fermentation. residues and (30- 80 mesh) distillers dried grains. The active ingredient is conven= Products such as me awe are suitable for incorponk lemly a game: y GQHVCHUGMII meth' tion into poultryfeedstuffs in order to obtain the. desired ods. such as-st1rr1ng,tun-rbl1ng,, and grmdmg In this mandosage 1 av e1 of active dmg by selectmg dlfiemm' camel's and by altenng' mg The amount of active ingredient required for effective t b d C v prophylacticcontrol of coccidiosis is very low. With remg concen ta 8 PrePare 9 F gard to poultry, results have been obtained by the Mable addltm feed my fl a mm administration of. a quantity of the active ingredient about to about the new cocclqlostattand equal to about .005'% to .05'% of the food consumed. prefiambly about -25% adsorbed on or mlxed with a Optimum results are, usually-obtained bythedaily admincamer' f 4 b Md i I t V istration of a quantity of active ingredient equal to about 1 m an .0075% to about .025%- of the foodconsumed. Such Zme comp ex may l are 9' a a relatively small amounts may be conveniently incorpogeneral manner. Two satisfactory formulations are derated in thc normal rat-Lon Prior to feeding the Poultry m below a 90 Although the prophylactic use is by far the more impor- Ingredlems' taut application of coccidi'ostati'c compounds, their use in a. 4,4-dinitrocarbanilide-3Pamino-as-triazine complex therapy of the disease is highly valuable. Larger conb. Corndistillers. dried grains centrations of up to about 0.1% of these new complexes c.- Wheat shorts may be employed therapeutically if an outbreak of the d. Dried vitamin B-mfermentation solubles disease-is'eneonnteredi The coccidiostatic activity of compositions containing various S arriind-aS-triiaz'i'ne-substituted urea complexes was experimentally demonstrated according, to the follow- Co'mpzJSi'tion.Each ound of the mixture. preparation contains 0.30 pound of coccidiost'at drug. In order to prepare 1000 pounds of feed premix the following 1 ing testz' I qudnl es re amp p I p Groups of ten two week old chicks were fed a mash P P01111148 4,4 feed containing from 0.01% to 0.04% of the active ingre- Zme comp ex dient uniformall dis ersed therein. After existin on b. 175 pounds corn distillers dried grains (through 30 the diet for each chick inoculated gwith mesh screen) 50,000 sporulatedi oocysts of E. tenella. In addition,

6. 455 pounds wheat shorts (30-80 mesh) d. 70 pounds dried vitamin B12 fermentation solubles groups of tm chicks were also infected but fed a diet (304w mesh) free of the active: ingredient and used as positive controls.

' V Stillother t td 1 hfll b-' v groups were reae separate y wit e su T total amounts of whgat F g stituted urea. compound and the B-amino-as-triazine comi fi g a g i poul t ig mlxe 1 40 pound and with. physical mixtures of the substituted urea 0 y a. an e remam f 6 g compound and the 3-arnino-as-triazine compound. The grams. After H'llXlllg for about two hours the material is p t d aft 1 d h f 1 ready for packaging; experiment was termina e er: mocu BUOB, an t e o lowing results were obtained; The oocyst count (num- Ingredients: 7 I be: of parasites of E.. tenella remaining): was determined 1.. 4,4-dinitrocarbanilide-3 amino-as-triaiine complex r sacrificing the birds and examining the infected organs b. Corn distillers dried grains microscopically;

I Percent Percent Mortality igg X Pereert Weight 7 Oomam Compound pmmdm Diet Treated Untreated Treated Untreated Treated Untreated 1: 0.1 o 40 I 20 34- so 45 4,i"-d.initrocarbanillde 0.05 0 40 28 a4 s6 is,

, 0.02.1: an 40' an as- 54 45 4,4-dinitrothiocarbanilide 0.1 111 i 20- 1-2. 4 v 1a.; Y 59 a0 fi-amino'as-triazinn. .t 0.1 20 17' Q 23' 26 v 15 A physical mixture 0!:

4,4' d.inltroearbanillde 0. 1

and 0 33 1a 5 20 56 2s 3-amino-as-triazine 0.1 a

2 a i-i a 22 4,4'-dlnitrocarbanilide-3-amino-astrlazine complex; 813: 8 g .7 g? g g 0.008 0 45 24.0 24 03 w, 43 4,4'-dlnitrothioearbanilide -3- amino-as-triazimcom iennnnu 0.1 0 20 1 (L1 1 10.1 73 so 0. Wheats horts V V V l Itwill benot'ed fromTableI that 4,4' -dinit rocarbanilide Dned tamm fermentatmn' solubles and 4,4'-'dinitrothiocarbanilide when administered sepa- Composition-Each pound of the mixture contains y 10 1 activity; but dactivity does no 0.2;5pound of 'coccidiostat. V approach that displayed by the complex. The complex- P p m i i o wms quantifies are p y in in; agentsofthemselvesare inactive. V J order make 995 Pounds Pmdmti The foll fig examples are intended to be illustrative a. 250. pounds 4,4 dinitmcatbanilide-3'-amino-astriaiineonly and may be or modified without departing complex 75 from the spirit and. 'sco'peof this invention.

Example 1 4,4'-DINITROCARBANILIDE- 3-AMHVO-AS-TRIAZINE COMPLEX amino-as-triazine complex weighed 784 g. (98.2%), and v melted with decomposition at 268-269 C.

Analysis-For C1sH140sNa (1:1 molar complex):

Calcd.: N, 28.13; percent 3-amino-as-triazine=24.l. Found: N, 27.55; percent 3-amino-as-triazine=24.l

(by u. v. analysis) x NHiiNH R N\\N NHiiNH N\ R A l g Q \T i i R I R N/ NH,

0,N N01 NANH:

Among the characteristic bands in the infra red spectrum of the complex is one at 2.9 ,u. and another at 9.4 a,

Example 2 4,4.'-DINITROTHIOCARBANILIDE-3-AMINO-AS-TRIAZINE COMPLEX S NH NH N 0 0 0 'i'l OrN NO: N NH:

8 flmn imzg N OQN No, NANH' 6.36 g. (0.02 mole) of 4,4'-dinitrothiocarbanilide was suspended in 120 ml. of ethylene glycol dimethyl ether. To this suspension was added 2.5 g. (0.026 mole) of 3-amino-as-triazine dissolved in ml. of warm ethanol. Within one minute the suspended solid began to change in color and texture. After five hours stirring at room temperature, the complex was filtered, washed with absolute alcohol, and dried to constant weight (7.05 g.).

The 3-amino-as-triazine complex of 4,4-dinitrothiocarbanilide thus prepared melted to a reddish brown liquid at 195-196 C.

Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.

tsulfur.

e What is claimed is: v 1. A compound of the formulawherein R is selected from the group consisting of hydrogen and lower alkyl groups, R' is an electron withdrawing group and X is selectedfrom the group consisting of oxygen and sulfur.

2. A compound of the formulawherein R is selected from the group consisting of hy drogen and lower alkyl groups and R is an electron withdrawing group, at least one R being a nitro group and X is selected from the group consisting of oxygen and 3. A compound of the formulawherein R is selected from the group consisting of hydrogen and lower alkyl groups and X is selected from the groupconsisting of oxygen and sulfur.

4. 4,4'-dinitrocarbanilide 3-amino-as-triazine complex.

5. 4,4-dinitrothiocarbanilide-3-amino-as-triazine complex.

6. The process which comprises reacting a compound represented by the formula-.-

wherein R is selected from the group consisting of hydrogen and lower alkyl groups, R is an electron withdrawing group and X is selected from the group consisting of oxygen and sulfur with a compound represented by the formula- I R NXNH:

wherein R is as above to form a complex represented by the formulawherein R, and R and X are as above.

7. The process which comprises reacting a compound represented by the formula wherein R is selected from the group consisting of hydrogen and lower alkyl groups, R is an electron withdrawing N NHa menses.

7 group, at least one R being a 'nitro group and Xis selected from the group consistingof oxygen and sulfur with a compound represented by the fbrrnulan N NH, wherein R is as above to form a complex represented by thefonnulawherein R, R and X are as above.

8. The process which comprises reacting a compound represented by the formulawherein R is selected from the group consisting of hydrogen and lower alkyl groups and X is selected from the group consisting of oxygen and sulfur with a compound represented by the formula-- no n mm wherein R is as above to form as complex; represented by the tlorrnula e JNH INHQ R R r om 3 i N0: R N Nm wherein R and X are as above.

wherein. R is selected from the group consisting of hydrogen and lower alkyl groups, R is an electron withdrawing group and X. is selected from the. group consisting of oxygen and; sulfur. 7

1:2,. A composition I useful, against, coccidiosis; which comprises an animal fcedstutf and. a compound represented: by the formula- R. wherein R is selected from the group consisting of hydrogen and lower alkyl groups, R is an; electron withdrawing group and X is selected from the group consisting of oxygen and sulfur.

13'. A composition useful against coccidiosis which comprises 4g4."-di'nitrocarbanilide 3-amino-as-triazine com- 1 plex, intimately dispersed in an inert carrier.

14. A composition useful against coccidiosis which comprises 4,4-"'-dinitrothiocarbanilid'e- 3'-amino-as-triazine complex intimately-"dispersed in an inert carrier.

No references cited. 

11. A COMPOSITION USEFUL AGAINST COCCIDIOSIS WHICH COMPRISES AN INERT CARRIER AND A COMPOUND REPRESENTED BY THE FORMULA- 